+IS IT ME OR IS IT HOT IN HERE? MENOPAUSE, MOOD & COGNITION

Neill Epperson, M.DProfessor Psychiatry and Ob/Gyn

Director, Penn Center for Women’s Behavioral WellnessDirector, Penn PROMOTES Research on

Sex and Gender in HealthDirector, Penn BIRCWH Program

Perelman School of Medicine at theUniversity of Pennsylvania

NAS Workshop on Women’s HealthMarch 7, 2018

Sex Differences: Lifespan Approach

Sexual Differentiation Of the Brain Begins in Prenatal Life

Bale & Epperson, NPP (2017) 42:386-396

Sexual Differentiation Of the Brain Begins in Prenatal Life

Bale & Epperson, NPP (2017) 42:386-396

Sex and Gender: Binary or Mosaic?

First TrimesterSecond and Third Trimesters

MALE FEMALE Masculine Feminine

ORGANIZATIONAL EFFECTS OF SEX STEROIDS

PUBERTY PREGNANCY MENOPAUSE

PRE-PUBERTY ANDROPAUSE

Gonadal Steroids Across the Lifespan: Activational Effects of Sex Steroids

HOW DOES THIS IMPACT HEALTH?

DEPRESSIONMIGRAINES

PANICPTSD

OPIATE/BZ ABUSE

ALZHEIMERS DZ

IMPULSE CONTROL D/O ALCOHOLISM

CARDIOVASCULAR DZ

BLADDER OUTLET OBSTRUCTION

DRY EYES

THYROIDITISMULTIPLE SCLEROSIS

SCLERODERMA, LUPUS

STRESS URINARY INCONTINENCECHROHN’S DISEASE

RHEMATOID ARTHRITIS

IRRITABLE BOWEL SYNDROME

ANOREXIA BULIMIA

OSTEOPOROSIS

BREAST CANCER

SCHIZOPHRENIA

AUTISMDYSLEXIA

INTERSTITIAL CYSTITIS

LUNG CANCERCOPD

ANKYLOSING SPONDYLITIS

TYPE I DIABETES

OBESITY (DEVELOPED NATIONS) OBESITY (DEVELOPING NATIONS)GALLBLADDER DISEASE

BLADDER CANCER

ANTISOCIAL PD

SUICIDE COMPLETERS

CHRONIC PAIN

OCD

SPORTS INJURY

CNS LYMPHOMA

HODGKINS DZ

OBESITY

ASTHMA

ECZEMA

EPILEPSYXY XX

ADHD

AGE, SOCIETY, HORMONES

Hormones & the Female Lifespan in 10 minutes

Periods of Risk Premenstruum Perinatal Perimenopause

Hormones & the Female Lifespan in 10 minutes

What do hormones contribute?Ovarian hormones Stress hormones

Hormones & the Female Lifespan in 10 minutes

Disparities in women’s health?

HORMONE EFFECTS: 101

NEUROCHEMISTRY

STRUCTUREFUNCTION

BEHAVIOR

ESTRADIOL

PROGESTERONE NEUROCHEMISTRY

INFLAMMATION

SerotoninDopamine

NorepinephrineGlutamate

Acetylcholine

Estradiol Effects: Serotonin

Tryptophan hydroxylase mRNA (1)

Clearance of 5-HTMAO Activity (2)

1) Sanchez RL et al., (2005) Mol Brain Res 135”194-203.2) Benmansour S et al., (2009) Neuropsychopharm 34:555-643) Kugaya A et al., (2003) AJP 160:1522-244) Shively & Bethea, J Pharmacogenomics, 20035) Murrough et al., (2011) AGP 68:892-90

Post-synaptic 5HT-2A receptor density.3

potency of estradiol on TPH2 gene expression.4

5HT1A receptor binding.5

Age, Stress, Estrogen: Impact on Neuronal Plasticity and Learning & Memory

Age, Stress, Estrogen: Impact on Neuronal Plasticity and Learning & Memory

Progesterone, ALLO & the GABA-A Receptor Potent GABA-A receptor

agonist. Alcohol Benzodiazepines Barbiturates

Increased synthesis when under acute stress.

Belelli et al., (2005) Nat Rev Neurosci 6:565-75Pinna et al., (2009) Curr Opin Pharm, 9:24-30

THE FLEXIBLE FEMALE BRAIN

PUBERTY PREGNANCY MENOPAUSE

Timing of Stress: Regional Impact

3-5 years old

Teicher & Samson, AJP 2013 170:10, 1114-1132

9-10 years old

14-16 years old

mid-corpus callosum

hippocampus

Prefrontal Cortex

Timing of Stress: Regional Impact

3-5 years old

Teicher & Samson, AJP 2013 170:10, 1114-1132

9-10 years old

14-16 years old

mid-corpus callosum

hippocampus

Prefrontal Cortex

THE MENOPAUSE TRANSITION:

ON AVERAGE, GIRLS BORN TODAY WILL LIVE A 3RD OF THEIR LIFE IN THE

POSTMENOPAUSE

Cognition Across Natural Menopause

Ellen Freeman, Ph.D.

Mary Sammel, Ph.D.

Penn Ovarian Aging Study Prospective community cohort study of 436 women

50% Caucasian, 50% African American; Philadelphia County

Enrolled as premenopausal women and followed for 14 years

Followed across menopause stages: Premenopause: Regular cycles, no change, Late Premenopause: >7days change in cycle length Early Transition: One skipped cycle Late transition: amenorrhea for 3-11 months Postmenopause: amenorrhea for 12 months Ellen Freeman, Ph.D.

VERBAL MEMORY PERFORMANCE DECLINES ACROSS THE MENOPAUSE TRANSITION

.

Epperson, Sammel, Freeman (2013) JCEM 98(9)3929-3838

POSTM

ENO

PAUSE

EARLY TRANSITIO

N

LATE TRANSITIO

N

IMMEDIATE RECALL DELAYED RECALL

PREM

ENO

PASU

SE

PREM

ENO

PAU

SE

VERBAL MEMORY PERFORMANCE DECLINES ACROSS THE MENOPAUSE TRANSITION

.

Epperson, Sammel, Freeman (2013) JCEM 98(9)3929-3838

POSTM

ENO

PAUSE

EARLY TRANSITIO

N

LATE TRANSITIO

N

IMMEDIATE RECALL DELAYED RECALL

PREM

ENO

PASU

SE

PREM

ENO

PAU

SE

Executive Function in Women after Risk Reducing Salpingo-Oophorectomy (RRSO)

800 women post-RRSO recruited primarily via internet through advocacy group Facing our Risk of Cancer Empowered (FORCE)

Completed online…. Self-report of executive function using the

Brown Attention Deficit Disorder Scale. Objective measures of cognition using

the Penn Computerized Neuro-cognitive Battery (CNB).

Adverse Childhood Experiences Questionnaire (ACE-Q)

Risk-Reducing Salpingo Oophorectomy (RRSO)

Susan Domcheck

Sheila Shanmugan

Assessing Executive Functions

BROWN ATTENTION DEFICIT DISORDER SCALE (BADDS)1) ORGANIZATION AND ACTIVATION FOR WORK2) ATTENTION AND CONCENTRATION3) MAINTAING ALERTNESS AND EFFORT AND PROCESSING SPEED4) MANAGING AFFECTIVE INTERFERENCE5) WORKING MEMORY AND ACCESSING RECALL

Thomas Brown

HOW ARE WE QUANTIFYING EARLY LIFE ADVERSITY?

Adverse Childhood Events (ACE)-Questionnaire developed and used in the collaborative study between the CDC and Kaiser-Permanente in San Diego area. 3 Questions about abuse (physical, emotional and sexual) 2 Questions regarding neglect (physical and emotional) 2 Questions regarding separation from parent/family member 3 Questions regarding household dysfunction (violence, substance

abuse, parental mental illness

“Stressed” group are those with > 2 ACEs Pre-pubertal period (birth to 2 years prior to menarche)

Russo SJ et al. (2012) Nat Neurosci. 12(11):1475-84Felitti V. et al., (1998) Am J Prev Med, 14(4):245-258. .

Organization/ActivationFor Work

Attention/Concentration

Alertness/Effort/Processing Speed

Managing Affective

Interference

Working Memory/Accessing Recall

a) b)

Tota

l BAD

DS S

core

*p<0.05, **p<0.01, ***p<0.001

*** ** ** ** *** *

Childhood Adversity Impact on Executive Function after Oophorectomy

***

a) b)* **

*p<0.05, **p<0.01, ***p<0.001

Objective Findings: Sustained Attention and Working Memory

Mediator:Mood Symptoms

Independent Variable:ACE

Dependent Variable:CPT Performance

β=2.1p=0.0002

β=-0.01p=0.001

β=-0.09, p=0.08a

Mediator:Mood Symptoms

Independent Variable:ACE

Dependent Variable:N-back Performance

β=1.9p=0.0006

β=-0.006p=0.2

β=-0.16, p=0.01a

Mediator:Mood Symptoms

Independent Variable:ACE

Dependent Variable:Total BADDS

β=2.1p=0.0003

β=2.8, p=0.08a

a)

b)

c)

β=-0.1, p=0.03b

a Direct effect of ACE on dependent variableb Total effect of ACE on dependent variable

β=7.1, p=0.0005b

β=-0.17, p=0.007b

MEDIATION ANALYSIS

MOOD (ANXIETY AND DEPRESSION) SYMPTOMS WERE SIGNIFICANT

MEDIATORS OF THE EFFECTS OF ACE

Subjective report of executive function difficulties (63%).

Objective measure of sustained attention (21%).

But not, working memory.

(β=2.1, p<0.0001)

Enduring Effects on Brain?

Sheila Shanmugan James Loughead

ACEs are associated with enduring effects on brain function, response to neurotransmitter and hormone manipulations

Shanmugan S, Loughead J, Cao W, Sammel MD, Satterthwaite TD, Ruparel K, Gur RC, Epperson CN.

Neuropsychopharmacology. 2017 Apr 12. doi: 10.1038/npp.2017.64. [Epub ahead of print]

ACEs are associated with enduring effects on brain function, response to neurotransmitter and hormone manipulations

Sheila Shanmugan James Loughead

Shanmugan S, Satterthwaite TD, Sammel MD, Cao W, RuparelK, Gur RC, Epperson CN, Loughead J.

Psychoneuroendocrinology. 2017 Jul 14;84:197-205.

Could natural changes in inflammation unmask vulnerability?

Loss of estradiol at menopause is associated with a rise in pro-inflammatory cytokines. Cardiovascular disease Osteoporosis Obesity Depression

Prepubertal ACE x Cytokine x Menopause Stage: Impact on Cognitive Measures

DIGIT SYMBOL

SYMBOL COPY

DELAYED RECALL

IMMEDIATERECALL

hsCRP 0.482 0.401 0.742 0.023IL-1β 0.327 0.874 0.382 0.027IL-6 0.02 0.037 0.016 0.173

TNF-α 0.118 0.715 0.029 0.025Included in the model: Age, race, BMI, Smoking status, depression severity

Processing Speed Verbal Memory

Date of download: 10/10/2015 Copyright © 2015 American Medical Association. All rights reserved.

From: Longitudinal Pattern of Depressive Symptoms Around Natural Menopause

JAMA Psychiatry. 2014;71(1):36-43. doi:10.1001/jamapsychiatry.2013.2819

Ellen Freeman, Ph.D.

Date of download: 10/10/2015 Copyright © 2015 American Medical Association. All rights reserved.

From: Longitudinal Pattern of Depressive Symptoms Around Natural Menopause

JAMA Psychiatry. 2014;71(1):36-43. doi:10.1001/jamapsychiatry.2013.2819

Ellen Freeman, Ph.D.

Menopause Onset Depression2-3 times

Recurrent Depression4-5 times

Can adverse childhood experiences lead to risk for first episode of major depressive disorder in the menopause transition.

Contacted 243 original POAS Participants.

Administered the ACE Questionnaire. Lifetime Incident Perimenopause Depression

ACE & MDD: Impact of number and pubertal status

Epperson, et al. J Clin Psychiatry. 2017 Mar;78(3):e298-e307.

ACE & MDD: Impact of number and pubertal status

Epperson, et al. J Clin Psychiatry. 2017 Mar;78(3):e298-e307.

In this sample, most commonly reported single ACE was… Household substance abuse Divorce Separation

Critical Windows Across Development

Bale & Epperson, Nature Neuroscience, 2015

X X X XSEX/GENDER SEX/GENDER SEX/GENDER

SEX/GENDER

SUMMARY Sex differences are present at birth Impacting risk for neuropsychiatric and developmental

disorders. ”Life” then interacts with this “substrate” to lead to risk and

resilience for psychiatric disorders. Stressors/adversity/trauma Reproductive hormones: static and fluctuating Gender roles and related experiences Lifestyle factors Health factors

Critical to consider reproductive stage, hormonal status AND stress history when studying women’s health.

KoshaRuparel

Sheila Shanmugan

Ellen Freeman

Allie Mott

Kathryn Czarkowski

Mark Elliot

Ravi PNR Ravi ReddySarah

Mathews

Tom Brown

Susan Domcheck

Joanna Marks

Stephanie Criniti

Emily Lipner

Jessica Podcasy

Connie BradyCarrie

Malanga

Brendan McGeehan

Emily Lipner

GiannaMelendez

James Loughead

Katie Morrison

Tracy Bale

Claudia Iannelli

Mary Sammel

Liisa HantsooDeb Kim

JeanetteBradley Ruben Gur

Lindsay Sortor

Grace Ewing Raisa Raina

Hillary Nguyen

Sara Kornfield

Andrew Siegel

And our Funding Sources!

Questions and Answers